In normal cells, the phosphatidylinositol-3-kinase (PI3K) is a regulator of multiple cellular functions, including protein synthesis and glucose metabolism, cell survival and growth, proliferation, cellular resilience and repair, cell migration, and angiogenesis. There is substantial evidence that in many tumors the PI3K signaling pathway is constitutively activated. Activation of the PI3K pathway via amplifications or mutations in the catalytic subunit (PIK3CA) or inactivation of negative regulators (e.g., PTEN) results in constitutive signaling and oncogenicity. Deregulation of the PI3K pathway is established to be one of the most frequent occurrences in various human cancers, including but not limited to pancreatic cancer, breast cancer and lung cancer.
The specific pyrimidine derivative compound of formula (I)
and its pharmaceutically acceptable salts are phosphatidylinositol-3-kinase (PI3K) inhibitors which may be used for the treatment of cancer. The compound of formula (I) has the chemical name 4-(trifluoromethyl)-5-(2,6-dimorpholinopyrimidin-4-yl)pyridin-2-amine. These compounds and their preparation are disclosed in WO2007/084786. Such pyrimidine derivative is proven to be an effective PI3K inhibitor, e.g. WO2007/084786 and S. Maira et al, Molecular Cancer Therapeutics 11:317-328 (2012), that displays broad activity against a large panel of cultured human cancer cell lines.
Administration of pharmaceutical agents via the oral route is advantageous to other administration routes (e.g., parenteral) because it allows self-administration by patients instead of administration by a physician, nurse or paramedical personnel.
However, the PI3K inhibitor compound 4-(trifluoromethyl)-5-(2,6-dimorpholinopyrimidin-4-yl)pyridin-2-amine and its pharmaceutically acceptable salts are difficult to formulate due to its physiochemical properties, and it is not trivial to make solid pharmaceutical compositions in a reliable and robust way. For example, this compound exhibits poor flowability and significant sticking tendency. Due to these physiochemical properties, it has been found that this compound is difficult to formulate into pharmaceutical compositions. Even when formulated with common lubricants (e.g., magnesium stearate), the compound remains sticky and is difficult to handle in a tableting machine. Other formulations of this compound showed poor compressibility. Accordingly, a suitable and robust solid pharmaceutical composition overcoming the above problems related to the properties of the compound 4-(trifluoromethyl)-5-(2,6-dimorpholinopyrimidin-4-yl)pyridin-2-amine and its pharmaceutically acceptable salts needs to be developed.
Surprisingly, it has been found that a robust solid pharmaceutical composition comprising the compound 4-(trifluoromethyl)-5-(2,6-dimorpholinopyrimidin-4-yl)pyridin-2-amine or a pharmaceutically acceptable salt thereof can be prepared conveniently using roller compaction when sodium stearyl fumarate is used as a lubricant. These solid pharmaceutical compositions overcome the foregoing problems and exhibits no or minimal sticking tendency and sufficient compressibility and hardness for the reliable and robust delivery of this compound or its pharmaceutically acceptable salts to patients in need thereof.